U.S. patent application number 13/190398 was filed with the patent office on 2013-01-31 for sustained release oral matrix and methods of making thereof.
The applicant listed for this patent is Gaurav Thakersi Tolia. Invention is credited to Gaurav Thakersi Tolia.
Application Number | 20130028955 13/190398 |
Document ID | / |
Family ID | 47597387 |
Filed Date | 2013-01-31 |
United States Patent
Application |
20130028955 |
Kind Code |
A1 |
Tolia; Gaurav Thakersi |
January 31, 2013 |
SUSTAINED RELEASE ORAL MATRIX AND METHODS OF MAKING THEREOF
Abstract
A solid dosage form suitable for forming a tablet for the
containment and delivery of medicament is provided wherein the
matrix forming material is a pressure sensitive adhesive, present
in the amount from about 0.1 to about 40 weight %, based on the
total weight of the composition. The dosage form is comprised of
the medicament and a water-insoluble polymer silicone pressure
sensitive adhesive and allows release of the medicament in a
controlled fashion depending on simple parameters such as weight
percent of the polymer silicone adhesive. A sustained release
dosage form is provided for delivery of medicament wherein the
release rate of medicament does not depend on the dissolution
medium of the pH. Another aspect of invention is formation of solid
tablets of poorly compressible material and the method for making
the solid composition. The dosage form for this invention s
particularly suitable for oral dosage forms.
Inventors: |
Tolia; Gaurav Thakersi;
(Cincinnati, OH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Tolia; Gaurav Thakersi |
Cincinnati |
OH |
US |
|
|
Family ID: |
47597387 |
Appl. No.: |
13/190398 |
Filed: |
July 25, 2011 |
Current U.S.
Class: |
424/450 ;
424/465; 514/180; 514/523; 514/567; 514/629; 514/772; 514/772.1;
514/772.6; 514/777; 514/784 |
Current CPC
Class: |
A61K 31/167 20130101;
A61K 31/196 20130101; A61P 31/10 20180101; A61P 3/10 20180101; A61P
9/06 20180101; A61K 9/2027 20130101; A61K 31/573 20130101; A61K
31/277 20130101; A61P 35/00 20180101; A61P 29/00 20180101; A61P
31/04 20180101; A61P 31/12 20180101; A61P 3/04 20180101; A61P 33/02
20180101; A61K 31/60 20130101; A61P 25/06 20180101; A61P 7/02
20180101; A61P 25/08 20180101; A61K 9/2036 20130101 |
Class at
Publication: |
424/450 ;
514/629; 514/523; 514/567; 514/180; 514/772.1; 514/772.6; 514/784;
514/772; 514/777; 424/465 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 31/277 20060101 A61K031/277; A61K 31/196 20060101
A61K031/196; A61K 31/573 20060101 A61K031/573; A61K 47/34 20060101
A61K047/34; A61K 47/32 20060101 A61K047/32; A61K 47/12 20060101
A61K047/12; A61K 47/10 20060101 A61K047/10; A61K 47/26 20060101
A61K047/26; A61P 29/00 20060101 A61P029/00; A61P 9/06 20060101
A61P009/06; A61P 31/04 20060101 A61P031/04; A61P 31/12 20060101
A61P031/12; A61P 7/02 20060101 A61P007/02; A61P 3/10 20060101
A61P003/10; A61P 25/08 20060101 A61P025/08; A61P 35/00 20060101
A61P035/00; A61P 31/10 20060101 A61P031/10; A61P 25/06 20060101
A61P025/06; A61P 33/02 20060101 A61P033/02; A61P 3/04 20060101
A61P003/04; A61K 31/167 20060101 A61K031/167 |
Goverment Interests
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Research partly funded by the NSF IGERT Program in
Bio-Applications of Membrane Science and Technology (Grant
#0333377) at the University of Cincinnati.
Claims
1. A solid tablet for controlled release of active medicaments
comprising one or more active pharmaceutically agent in an amount
sufficient to provide a therapeutic effect when administered and at
least a pressures sensitive adhesive.
2. The solid tablet of claim 1 wherein the pressure sensitive
adhesive is a silicone pressure sensitive adhesive selected from a
silicone/resin copolymer with silicon-bonded hydroxyl radicals, a
silicone/resin copolymer with end capped silicon-bonded hydroxyl
radicals and mixtures thereof.
3. The solid tablet of claim 2 wherein the pressure sensitive
adhesive is an silicone pressure sensitive adhesive selected from a
silicone/resin copolymer and has 40 to 70 parts by weight of at
least one resin copolymer and 30 to 70 parts by weight of
polydiorganosiloxane comprising ARSiO units.
4. A composition according to claim 2, wherein the silicone/resin
copolymer is prepared by polycondensation of the silanol endblocked
polydialkylsiloxane with a hydroxyl end-blocked silicate resin.
5. The solid tablet of claim 1 wherein the pressure sensitive
adhesive is an acrylic pressure sensitive adhesive comprising about
5 to about 100 weight percent of (meth)acrylic acid copolymer
cross-linked with a crosslinking agent.
6. The solid tablet of claim 1 wherein the active pharmaceutical
agent is selected from the group consisting of analgesics,
anti-inflammatory agents, antihelmimthics, anti-arrhythmic agents,
anti-bacterial agents, anti-viral agents, anti-coagulants,
anti-depressants, anti-diabetics, anti-epileptics, anticancer
agent, anti-fungal agents, anti-gout agents, antihypertensive
agents, anti-malariale, anti-migrainc agents, anti-muscarinic
agents, anti-neoplastic agents, erectile dysfunction improvement
agents, immunosuppressants, antiprotozoal agents, anti-thyroid
agents, anxiolytic agents, sedatives, hypnotics, neuroleptics,
(3-Blockers, cardiac inotropic agents, corticosteroids, diuretics,
anti-parkinsonian agents, gastro-intestinal agents, histamine
receptor antagonists, keratolytics, lipid regulating agents,
anti-anginal agents, cox-2 inhibitors, antioxidant agent,
leukotriene inhibitors, macrolides, muscle relaxants, nutritional
agents, opioid analgesics, protease inhibitors, sex hormones,
stimulants, muscle relaxants, anti-osteoporosis agents,
anti-obesity agents, cognition enhancers, anti-urinary incontinence
agents, nutritional oils, anti-benign prostate hypertrophy agents,
a hormone, a steroid, steroid antagonist, a vitamin, essential
fatty acids, non-essential fatty acids, and mixtures thereof.
7. The solid tablet of claim 6 wherein the active pharmaceutical
agent is poorly compressible.
8. A solid tablet for controlled release of active medicaments of
claim 1 wherein the pressures sensitive adhesive comprises from
about 0.1 to about 40 weight %, based on the total weight of the
composition for aiding compression and controlling medicament
release.
9. A solid tablet for controlled release of active medicaments
comprising one or more active pharmaceutically agent in an amount
sufficient to provide a therapeutic effect when administered, an
excipient and at least a pressures sensitive adhesive.
10. A solid tablet for controlled release of active medicaments of
claim 9 wherein the pressures sensitive adhesive comprises from
about 0.1 to about 40 weight %, based on the total weight of the
composition, the active pharmaceutical agent comprises from about
10 to about 99 weight % based on the total weight of the
composition and the excipient comprises from about 5 to about 70
weight % of the total weight of the composition.
11. A method according to claim 1 for controlled and sustained
release of medicaments for oral drug delivery delivered from a
tablet compromising of silicone pressure sensitive adhesive and at
least one active medicament.
12. A method according to claim 1 for controlled and sustained
release of medicaments for oral delivery from a tablet along the
oral route comprising of a pressure sensitive adhesive, at least an
active agent and at least one water soluble excipient comprising
of: (i) an anti-sticking agent, a glidant, a flow promoter, a
lubricant, an anticoagulant, an antifoaming agent, an antioxidant,
a binder, a buffering agents, a chelating agent, a coagulant, a
colorant, a cryoprotectant, a diluent, a filler, a disintegrant, a
flavorant, or sweetner, a plasticizer, a preservative and mixtures
thereof.
13. A composition of claim 9, wherein a solubilizing agent is added
to the oral tablet comprises from about 1 to about 70 weight
percent of the total composition.
14. A composition according to claim 9, wherein the solubilizing
agent is a complexing agent, surfactant, liposome, PEG derived
fatty acids, buffering agent, glycols or sugars.
15. A solid tablet of claim 1, wherein the active pharmaceutical
agent is a salt form of the active agent.
16. A solid tablet of claim 1, wherein the active pharmaceutical
agent is a weak acid, weak base, non ionizable or mixtures
thereof.
17. A method for preparing the oral tablet comprising the steps of:
(i) dissolving the pressure sensitive adhesive in appropriate
solvent (ii) forming a suspension of medicament in the
adhesive/solvent solution (iii) drying the suspension to obtain a
solid matrix (iv) compressing the matrix to form required shape and
size of the oral dosage form
18. A method according to claim 17, wherein the solvent used for
dissolving the polymer is selected consisting of hydrocarbon
solvents, volatile silicones, non-hydrocarbon solvents and mixtures
thereof.
19. A method for preparing the solid tablet according to claim 1,
wherein the adhesive (i) is a curable adhesive, cured either by
using catalytic reaction, heat, oxidation, light or combinations
thereof (ii) is a cross-linked pressure sensitive adhesive.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] Non-provisional patent application filed using Attorney
Docket No: 110-0290N 2010 Feb. 28 with the Title of the Invention:
"pH-Independent Sustained Release Oral matrix and Methods of Making
Thereof"
THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT
[0003] The application for patent for the claimed invention
discloses the names of Inventor Gaurav Tolia, an employer of the
University of Cincinnati and the University of Cincinnati where the
claimed invention was undertaken as the parties to the joint
research agreement.
INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A COMPACT
DISC
[0004] Not Applicable
BACKGROUND OF THE INVENTION
[0005] (1) Field of the Invention
[0006] The present invention relates generally to the use of
pressure sensitive PSA for the formation of oral solid matrix
tablet of medicament(s) not requiring any additional excipients for
aiding compression and release, and particularly, to a sustained
release dosage form matrix of active agent(s) providing drug
release for an extended period of time after administration.
[0007] (2) Background of the Invention
[0008] Generally oral administration of medicaments remains the
most convenient and preferred route. A variety of substances, such
as pharmaceutical active drugs and nutraceuticals are often
formulated in a solid dosage form such as tablets, coated tablets,
pastilles, pellets, granules and the like. It is herein referred as
the term "solid dosage form" to a presentation, which is suitable
in particular for oral, buccal or rectal administration in any of
desired forms and shapes. The term "tablet" is a term well
understood by not only those skilled in the art but also to the
general public at large. Generally, the term "tablet" includes not
only tablets which are oval or cylindrical in shape per se but also
includes similar discrete bodies, perhaps of other shapes such as
donut for example and sometimes known by different names, such as
"caplets" (e.g. capsule-shaped tablets), lozenges, and pills.
Herein it is referred as a mixture of medicament with the pressure
sensitive PSA and other excipients if required which have been
brought together by various ways and compressed using one or more
apparatus known to those skilled in the art so that the
medicament(s), the polymer and excipient(s) becomes a compacted
"tablet" which is free of chipping, cracking or lamination and the
"tablet" is capable to persist normally encountered handling
conditions. This compacted "tablet" is able to resist
disintegration at the desired time, site, or combination of
both.
[0009] Generally, tablets contain a medicament and at least an
excipient such as lubricant, granulating agent, binders,
antiadherents, glidants or combinations thereof in order to form a
tablet of poorly compressible powder for the formation of a tablet
which is free from defects such as chipping, cracking or lamination
for example. The use of "tableting aid" are generally known to
those skilled in the art of making tablets. Additionally, the
process of making tablets using direct compression involves process
of granulation (wet or dry) of poorly compressible material. The
processes used for making direct compression tablets of poorly
compressible medicaments is also known to those skilled in the art
of making tablets.
[0010] In a pharmaceutical context, a poorly compressible
medicaments are usually powders, which undergo elastic deformation
when compressed under high pressure using any equipment's used for
making solid dosage forms. During tablet manufacturing, solid
powders are compressed under high pressure in a punch and a die.
Poorly compressible powders deform under high pressure in a punch
and a die during tablet compression. On removal of the pressure
during ejection of the tablet from the die, the elastically
deformed powders undergo elastic recovery and expand. This is
supposed to be one of the causes leading to chipping, cracking or
lamination of the tablet on ejection from the tablet press
equipment. Those skilled in the art solve this problem by either
adding excipients such as binders, lubricants, glidants or
disintergrants or using processes which are known to those skilled
in the art. In addition, those skilled in the art also solve the
problem by using method to form granules of poorly compressible
powder. U.S. Pat. Nos. 5,370,878 and 5,733,578 discloses directly
compressible compositions of poorly compressible drug
acetaminophen. The disclosures use more than one excipient for
development of compressible acetaminophen. The process used is wet
granulation, which requires more than two steps to produce
compressible compacts, and is time consuming.
[0011] There is much art and skill in practicing the process of wet
granulation, which involves addition of medicament powder with
granulating fluid and forming a mix, which is then dried to obtain
granules. It is generally recognized that tableting aids are
required to form moist granules of fairly uniform size. The
granules are then forced through a mesh screen to maintain
homogeneity of mass. The process also requires drying the moist,
screened mash and it is important that the mass does not
agglomerate. binders, glidants, lubricants and disintegrants. The
terms of tableting aids such as "binders" means to one skilled in
the art a substance, which helps to bind the particles of powder
together in a form suited to compaction and compression. A
"glidant" means a substance which aid the medicament granules to
fill into the die before compression. A "lubricant" means a
substance, which helps the compressed tablets to leave the die and
not stick to the walls of the die. A "disintegrant" means a
substance, which helps the tablet to disintegrate in desired, site
or time.
[0012] One problem that is known with use of tableting excipients
such as granulating agents, binders, lubricants or glidants do not
necessarily sustain the release of the medicament. Sustained
release oral dosage form enhances the pharmacological benefits for
numerous medicaments. These sustained release dosage forms reduce
the frequency of administration of the dosage form. In order to
sustain medicament release from the tablet, the medicament is
coated using controlled release polymers known to those skilled in
the art. It is well know that coating of drug particles requires
expensive equipment's and requires many unit processes.
[0013] There is much art and skill in practicing the use of
polymeric materials such as celluloses, gums, and acrylates for
example for sustaining release rate of medicament. U.S. Pat. Nos.
5,733,031 and 5,858,412 describes compositions and methods for
producing directly compressible tablets for sustained release of
medicaments. None of the disclosures describe use of silicone PSA
or a pressure sensitive PSA for development of solid tablet of
poorly compressible drugs. It involves either coating the drug
powder with controlling polymer. The equipment's used for coating
drug powder are very expensive and are time consuming.
Alternatively, sustained release tablets are prepared by mixing of
powder of polymeric materials with medicament powder and
compressible into a tablet. Simple mixing of the polymer with
poorly compressible powder does not solve the commonly known
problem of capping, chipping or lamination of the compressed
"tablets". Therefore, use of polymers with known art and skill for
practice of sustained release oral tablets does not solve the
problem of formation of tablets with sufficient mechanical
strength, which can resist normally encountered handling
conditions. which can resist of poorly compressible drugs without
use of excipients such as glidants, lubricants, granulating agents
or binders. Therefore, oral tablets, which are designed to sustain
release of medicaments either, use coating, or polymers require
additional tableting excipients. There are no simple techniques for
making tablets of poorly compressible drugs without wet granulation
or requiring tableting excipients such as binders, glidants,
lubricants or granulating agents.
[0014] Therefore, there is a need for a polymer which can provide
controlled release oral delivery system where the drug release can
be controlled by inclusion of small amount of polymer which allows
formation of tablets with sufficient mechanical strength of poorly
compressible medicament. There is also an advantage if the polymer
used for controlling drug release and aiding compression does not
interact with the gastric environment and hence provide steady
reliable release rate of medicaments irrespective of the pH of the
gastric environment or the dissolution conditions.
[0015] Surprisingly, it now has been found that employing polymer
such as silicone pressure sensitive PSA provides compositions for
oral tablets containing poorly compressible drug acetaminophen. The
tablets produced showed sufficient mechanical strength and can
provide sustained release of incorporated medicament without
addition of known tableting excipients or requiring expensive
coating equipment's. Surprisingly, it is also found that addition
of silicone pressure sensitive PSA in oral tablet composition
allows release of medicament to remain unchanged irrespective of
the pH of the dissolution medium, ionic strength of the dissolution
medium or the presence of mechanical agitation of the dissolution
medium.
[0016] Use of pressure sensitive PSA for drug delivery application
to skin or devices is well known in the art. Generally PSA's are
used for adhering to a substrate or adhering two substrates. The
use of PSA's for adhesion is described for example in U.S. Pat.
Nos. 2,857,356, 5,234,957 and 3,797,494. "PSA"'s are generally
defined as materials which forms bond with the substrate when light
pressure is applied. It is well known to those in the art that
PSA's generally consists of an elastomer linked with suitable
resins. The elastomer is well known to be based on either acrylic,
butyl ether, vinyl ether, ethylene vinyl acetate, natural rubber,
nitriles, styrene block copolymers or silicone rubbers for example.
The process for mixing the PSA with the medicament to form an
adhesive device capable of adhesion is also generally well known in
the art. U.S. Pat. Nos. 2007/0,166,244 and 2006/0,142,411 discloses
invention related to use of silicone pressure sensitive adhesive
for delivery of tooth whitening agents or oral care substance to
the oral cavity. None of the disclosures relate to use of unique
properties of pressure sensitive adhesive for improving
compressibility of poorly compressible medicaments for oral
sustained drug delivery. Moreover, the disclosure do not relate to
sustained release of medicament along the gastro intestinal tract
for oral drug delivery. Herein, "oral drug delivery" refers to
delivery of drug along the gastrointestinal tract (GI). This is
although not limited to the oral GI system but it is also
applicable to rectal, buccal and oral cavity.
[0017] Surprisingly, it is now found that addition of solid
medicament or excipients in amount greater than 60 weight percent
in adhesive reduces the adhesive properties of the PSA's and the
formed solid matrix is compressible. This compressible solid matrix
of small amount of PSA(s) and medicament(s) without any tableting
excipient can be compressed under high pressure to produce tablets
of sufficient mechanical strengths.
SUMMARY OF THE INVENTION
[0018] The present invention is a solid composition capable of
forming tablets of sufficient mechanical strengths. The solid
composition comprises of pressure sensitive adhesive, in an amount
sufficient for formation of tablets with good mechanical strengths
when compacted: from 0.1 to about 40 weight % based on total weight
of the composition, wherein the medicament is the remaining
substance in the composition other then the PSA. Generally, the PSA
of the present invention includes a silicone tackyfying resin and
polyorganosiloxane
[0019] Another aspect of the present invention is the process for
preparing a solid composition and particularly one suitable for
tableting comprising of dissolving the PSA in a solvent in a
predetermined amount; addition of medicament powder at room
temperature; mixing to form a suspension of medicament in PSA
solution; drying of the suspension; compression of the dried
material to form a substantially homogenous matrix tablet free of
defects such as chips, cracks or lamination.
[0020] It is an object of the present invention to provide a solid
composition that is suitable for manufacture of tablets capable of
providing sustained release of medicament wherein the release rate
does not depend on the pH of the dissolution medium or presence of
mechanical agitation.
[0021] According to yet another aspect of the invention, the dosage
form does not depend on presence of buffers or tableting excipients
for the formation of tablets with sufficient mechanical strength or
to provide sustained release of medicaments.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)
[0022] FIG. 1 A) is an illustration of stereomicroscopic images of
the tablets showing chipping on edges when prepared using currently
used polymer, ethyl cellulose and poorly compressible drug
acetaminophen, and B) is an illustration of stereomicroscopic
images of the tablet free of chipping and cracking prepared using
polymer in this invention, a silicone pressure sensitive adhesive
(PSA) and poorly compressible drug acetaminophen produced according
to Example 1F and Example 2 respectively.
[0023] FIG. 2 shows mean of cumulative drug release after
dissolution testing in different pH medium from silicone PSA
tablets of different weight percent according to Examples 1F.
[0024] FIG. 3 shows mean verapamil hydrochloride drug release after
dissolution testing from silicone PSA tablets containing 20 weight
percent silicone PSA in different dissolution medium pH according
to Example 3.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The present invention is based on the unusual discovery that
solid matrix containing using silicone pressure sensitive adhesive
(PSA) are useful for formation of tablets under high pressure with
sufficient mechanical strengths of poorly compressible medicaments.
Herein is provided a solid oral matrix tablet specifically
containing at least above 0.1 weight percent of silicone PSA and
below 99.9 weight percent of one or more of pharmaceutical,
nutraceutical, veterinarian, cosmaceutical or dietary supplement
active medicament(s) and mixtures thereof. It is understood that
while the embodiments described refer to the use of silicone PSAs
and silicone PSA's in particular, other adhesives and PSA's which
are viscoelastic, inert, water-insoluble and capable of being
compressed under slight pressure can also be useful for formation
of solid oral tablets with sufficient mechanical strengths and in
providing sustained release of medicaments.
[0026] There is provided a novel use of pressure sensitive adhesive
materials for improving compressibility of poorly compressible
materials. Pressure sensitive adhesives can deform under slight
pressure, while elastic drug powders undergo elastic recovery when
compressed under pressure. Use of mixture(s) of deformable polymers
with elastic powders for direct compression enables improvements in
the properties of the formed tablet is described in this invention.
The novel use of these pressure sensitive adhesive materials
provides directly compressed tablets with excellent mechanical
properties of medicaments, which are poorly compressible. The
material is also hydrophobic, inert, water insoluble with low
surface energy and glass transition temperature. Hydrophobic and
low surface energy properties of the material are utilized for
novel application of coating the drug powder for oral sustained
release drug delivery by mixing the material directly with the
active medicaments.
[0027] Use of inherent properties of pressure sensitive adhesives
is utilized for a novel use, which allows improvement in drug
release characteristics suitable for oral drug delivery
application. The physiological conditions along the
gastrointestinal tract changes with respect to pH, ionic strength,
and the rate and extent of gastric motility. It is well know in to
those skilled in the art that oral controlled release drug delivery
systems require polymers to provide robust release rate. The
polymers used currently for oral controlled release are in glassy
state. These conventionally used polymer for commercial products of
oral controlled release include polymers that have glass transition
temperature above room temperature and are non-cohesive in nature.
Hydrophilic polymers known to those skilled in the art are
polymers, which swell, dissolve, erode or combinations thereof and
thereby provide controlled release rate after interacting with
water environment. The disadvantages of hydrophilic polymers
include uptake of large amount of water when exposed to aqueous
environment of the gastrointestinal tract. They also change their
state from glassy state to rubbery state when hydrated. In doing
so, they depend on the aqueous environment and hence are prone to
show effect of dissolution medium pH on drug release rate. There is
provided an improvement over hydrophilic polymers for controlled
oral release tablet using silicone pressure sensitive adhesive
where the release rate of drug from silicone PSA tablets do not
depend on the pH of the dissolution medium.
[0028] Use of the silicone pressure sensitive adhesives [PSA] is
the material described here for improvement in oral controlled
release tablets has low glass transition and are highly cohesive
material. Formation of matrix with the material provides
improvement because the cohesive nature of the material allows the
prepared tablet to sustain mechanical agitation of the
gastrointestinal physiology in form of peristalsis and gastric
motility and remain cohesive and not fall apart and loose its
controlled release mechanism. Non-cohesive polymers that are
currently used for controlled release and widely known to those
skilled in the art have high glass transition temperature (Tg). It
has been illustrated that matrix tablet prepared using non-cohesive
high Tg polymers are unable to sustain their drug release mechanism
on presence of mechanical agitation.
[0029] Silicone PSA is an exemplary matrix with necessary
characteristics because it has been utilized in commercial
transdermal, topical, wound care and medical devices and has been
tested for its biocompatibility and toxicology. Silicone PSAs have
also been used for transmucosal and transbuccal and for oral
applications. The inertness of silicones is useful and hence it is
used in over 50% of the cosmetic products as well as long for long
term implant applications. Silicone PSA is resistant to water and
does not absorb water. Normally encountered physiological medium
does not break down silicone PSA and therefore can be considered as
inert polymer. Due to inert and hydrophobic nature of silicone PSA,
the oral matrix tablet formed using silicone PSA is able to provide
sustained release of contained medicament(s) at same rate
irrespective of the pH of the dissolution medium (between pH 1.2
and 6.8).
[0030] Although silicone materials such elastomers, silicone
liquid, silicone adhesive has been known to provide sustained
release of active medicaments, pressure sensitive adhesives differ
in their properties which has not been utilized for direct
compression of poorly compressible drugs such as acetaminophen for
example. Use of silicone elastomers for sustained release is well
now to those skilled in the art. Use of pressure sensitive
adhesives for helping compression of poorly compressible drug
powder is not obvious. Adhesives can stick to substrates they come
in contact with and hence would not be obvious choice for use as a
material for oral direct compression process.
[0031] The process described here is an improvement in utilizing
the property of pressure sensitive adhesives for direct compression
by addition of solid drug powder in high loading with an adhesive.
By addition of high drug loaded powder which does not dissolve in
the solvent during mixing of adhesive and the drug powder, the
adhesion surface of the adhesive is taken by the drug powder. The
overall adhesion of the pressure sensitive adhesive (PSA) is
greatly reduced and the solid matrix does not stick to the die and
punches during compression. Silicone PSA as used in transdermal
drug delivery devices. Transdermal devices are prepared by
dissolving the drug in the solvent along with the adhesive. The
formed device is required to be sticky and adhere. The novelty in
this invention utilizes the fact that a reduction in adhesion of
PSAs can be achieved by suspending high drug loading powder in the
adhesive matrix. This process and the composition reduces the
disadvantages of adhesion properties of the adhesive. The
improvement then is shown where the compressibility properties of
adhesives are utilized for forming solid tablets.
[0032] Acetaminophen commonly known as paracetamol, is a widely
used analgesic and antipyretic drug, which is widely known to those
skilled in the art because of its poor flowability and
compressibility properties. It is often used alone or as
combination in commercially available products with drugs such as
tramadol hydrochloride, caffeine, pseudoephedrine, diphenhydramine,
pamabrom and butalbital. The commercially available form of
acetaminophen is the monoclinic powder form. This powder form of
acetaminophen is well known to undergoes particle fragmentation and
elastic deformation, which leads to capping and chipping of formed
tablets during tablet compression. Wet granulation is a routinely
employed procedure for improving compressibility of poorly
compressible drugs such as acetaminophen and it is well know to
those skilled in the art.
[0033] As illustrated in FIG. 1. tablets prepared using silicone
PSA do not show the problem of chipping, cracking or lamination. In
comparison, tablets prepared using rigid polymer ethyl cellulose
how chipping and cracking Also, the friability of silicone PSA
tablet is very low. The mechanical strength of silicone PSA tablet
is illustrated in example II. It has been illustrated that the
mechanical strength of these tablets formed using silicone PSA
containing poorly compressible drug acetaminophen is surprisingly
high. In comparison, mechanical strength of tablet containing ethyl
cellulose is low and shows high friability.
[0034] As illustrated in Example II, the contact angle of silicone
PSA tablet shows high value. This is improvement compared to use of
water insoluble hydrophobic polymer such as ethyl cellulose. High
hydrophobic surface provided by silicone PSA in this invention is
useful for sustaining release of water soluble drug acetaminophen
using as little as 5 weight percent of silicone PSA for 12 h. This
indicates that silicone PSA can serve as a matrix for development
of sustained release tablets and it can eliminate the
compressibility issues normally encountered when compressing poorly
compressible powders.
[0035] The process disclosed here is novel and simpler compared to
that known to those skilled in the art of coating. The process of
coating drug powder requires expensive equipment's and the coated
dug particles are required to be sieved after drying. In case of
silicone PSA, the particles are ready to be compressed and when
compressed, they show uniformity due to excellent spread ability of
silicone PSA over substrates.
[0036] Example IV shows an improvement in controlling drug release
rate by using silicone PSA due to the effect of dissolution medium
pH. Example VI shows an improvement for oral delivery for release
of medicament using silicone PSA when exposed to bio relevant
dissolution medium. Bio relevant dissolution medium as tested in
Example VI contain bile salts and lecithin in order to mimic fed
and fasted state of the aqueous environment in vivo. The silicone
PSA tablets tested under dissolution conditions shows that there is
no change in release rate of acetaminophen. Ethanol is sometimes
consumed by patients when a controlled release tablets is to be
required to be administered. Ethanol consumption has shown to
disrupt the mechanism of controlled release dosage form leading to
dose dumping and causing unwanted side effects of therapeutic
inefficacy. Silicone PSA tablets show that presence of ethanol does
not affect the drug release rate and drug release mechanism and
does not lead to dose dumping.
[0037] As illustrated in Example X, silicone PSA tablets when
exposed to mechanical stress do not show change in the drug release
rate. In comparison, conventional polymers, which are rigid and
glassy in state, do not sustain mechanical stress application.
Application of stress on ethyl cellulose tablets show burst release
indicating loss of controlled release mechanism. Silicone PSA is a
cohesive polymer and its use for oral delivery system where
mechanical stress is normally encountered due to gastric motility
and peristalsis. Use of cohesive polymer such as silicone PSA is
shown here as an improvement over conventional polymers known to
those skilled in the art for oral drug delivery.
[0038] The use of the improved material will reduce formulation
development time and effort to obtain appropriate composition for
eliminating chipping and cracking issues related to direct
compression of poorly compressible medicaments which are required
in high dose. The use of the improved material eliminates the need
for use of binders, lubricants, glidants or granulating's agents.
The use of the improved material also eliminates the need for use
of expensive and time consuming process of drug coating. Low
surface energy of the material ensures coating of drug powder and
the hydrophobic property of the silicone coating formed prevents
water from entering the matrix and hence provides sustained release
of medicament.
[0039] Therefore, the use of pressure sensitive adhesives and the
process disclosed herein reduce an improved material exhibiting
unexpected improvement in compressibility of poorly compressible
drug powder at high loading and also provide sustained release of
medicament which do not change depending on the outside dissolution
medium pH conditions.
Example I
Images of Tablets Formed Using Conventional Glassy Polymer in
Comparison to Silicone PSA Polymer Tablet
[0040] The present composition is prepared using conventional
polymer, ethyl cellulose that is an example of a glassy polymer
with high glass transition temperature. Ethyl cellulose is an
example of a polymer, which is widely used in oral controlled
release tablet formulations for development of sustained release
products. Tablets were prepared for this example by dissolving
about 2 g of ethyl cellulose in about 7 ml of ethyl acetate.
Acetaminophen powder was sieved and about 8 g of acetaminophen
powder was added to the vial containing ethyl cellulose or silicone
PSA solution. The vial was allowed to rotate for 4 h and the
suspension obtained was poured onto a fluoropolymer coated side of
the release liner. The suspension was allowed to dry overnight.
Weighed 500 mg portions of the dried matrix was compressed using a
13 mm flat-faced cylindrical die in a Carver press at 6.4 kN force
for 2 sec. The tablets obtained are illustrated in FIG. 1. The
composition of the tablets is 20 weight percent of polymer and 80
weight percent of acetaminophen. After the tablet preparation, the
obtained tablets were imaged using a stereomicroscopic to
investigate the effect of addition of glassy polymer for formation
of tablet of poorly compressible drug acetaminophen. From FIG. 1,
it can be seen that the tablets obtained using glassy polymer such
as ethyl cellulose does not produce tablet with good mechanical
strength. There is chipping of the tablet, which is not acceptable
for a good product.
[0041] The problem of chipping, cracking or lamination of tablets
prepared using ethyl cellulose is not exclusive. This problem has
been shown in examples for other currently used polymers and
excipients such as manifold, celluloses, or acrylates for example.
There is no benefit obtained by using glassy polymers such as ethyl
cellulose for development of directly compressible tablet of poorly
compressible drug such as acetaminophen suing simple procedure as
described in this example.
Example II
Mechanical Strength Evaluation of Silicone PSA Tablets
[0042] The mechanical properties of the formed tablet containing
various weight percent of silicone PSA and acetaminophen from
Example I may be evaluated using the procedure such as tablet
hardness and tablet friability. The hydrophobicity of tablet
surface may be evaluated using the technique of contact angle
measurement. Higher contact angle values indicate hydrophobic
surface. In order to measure tablet hardness, a tablet is placed
between two holders. The holders move to apply force on the tablet.
The force required to break a tablet is presented as tablet
hardness value. An average of three measurements are shown in Table
2. Tablet friability is measured by placing three tablets in a
revolving friability tester. In order to test friability of tablet
composition, three tablets were revolved for 100 revolutions. The
weights of the tablets before and after friability testing were
obtained. % Friability value may be calculated from the total
tablet weight of intact tablets before and after friability
testing. Contact angle measurements were performed using a
Rame-Hart Goniometer using sessile-drop method. A 5 ul drop of
water is placed on the surface of a tablet and the angle of water
droplet formed on the tablet surface is measured.
[0043] Tablet hardness of various tablets containing silicone PSA
is shown in Table 2. The tablet hardness increases as the weight
percent of silicone PSA in the tablet composition increases.
Silicone PSA is acting as a binder of poorly compressible drug
acetaminophen (APAP). Friability of tablet was measured using
friability tester and the results are shown from example 1A-F.
Increasing the silicone PSA composition above 5 weight percent
shows acceptable friability. A pharmaceutically acceptable value of
friability of a tablet is a value less than 1%. The friability of
silicone PSA tablet containing 20% weight polymer was compared with
standard conventional polymer ethyl cellulose based tablet. The
friability value of conventionally used polymer tablet of ethyl
cellulose was 4.3%, which is higher than pharmaceutically
acceptable value for a oral tablet. The contact angle of all the
silicone PSA tablets shown in Examples 1A-1F show high values. In
contrast, contact angle value on ethyl cellulose tablet shows a low
value of 44.1 degrees. Low contact angle value on ethyl cellulose
tablet indicate the difference between using a hydrophobic polymer
with high and low glass transition temperature and viscoelasticity
and spreading ability of the polymer film on solid drug powder
surface. Silicone PSA has low surface energy of 23 dynes/cm.sup.2,
and hence it is capable of spreading better as compared to rigid
polymer such as ethyl cellulose. These examples also signifies the
novelty in this invention of using polymer with low surface energy
and low glass transition temperature and its ability to provide a
hydrophobic surface for sustained release of water soluble drug in
addition to its ability to aid compression of poorly compressible
powders. The glass transition temperature of silicone PSA is -123
C.
Example III
Release of Acetaminophen from Silicone PSA Tablets
[0044] The effect of silicone PSA weight percent in tablet
composition on release rate of acetaminophen from the tablets was
studied using the following procedure. The results of acetaminophen
release from silicone PSA tablets are shown in Table 3.
[0045] The release rate of these formulations were carried out
using USP dissolution basket apparatus 1 (Vankel, Inc) using about
100 rpm stirring speed at about 37 C in about 900 ml of the
dissolution medium. The dissolution medium used was simulated
intestinal fluid with a pH of about 6.8. At predetermined time
intervals, 1 ml of sample was withdrawn and was analyzed to
determine acetaminophen concentration. Concentration of
acetaminophen in the dissolution medium was determined using a HPLC
method. A C8 column was used using mobile phase of 65% methanol and
35% water. Flow rate was 1 ml/min and the UV detection wavelength
was 254 nm. The results are reported as average of six tablets.
Results indicate that increase in silicone PSA composition in the
matrix decreases the release rate of acetaminophen from the tablet
matrix. Total weight of each tablet was 500 mg. The diameters of
the tablets were 13 mm.
[0046] It can be seen that increasing the amount of silicone PSA in
the composition decreases the release rate of acetaminophen from
the matrix. The results indicate the importance of silicone PSA in
controlling the release rate of active medicament, acetaminophen
from the silicone PSA tablet. Small amount of 5 weight percent of
silicone PSA is also capable of sustaining release of acetaminophen
for 8 h.
Example IV
Release of Acetaminophen from Silicone PSA Tablets in Different
Dissolution Medium pH
[0047] The effect of dissolution medium pH on drug release from
silicone PSA tablet was determined using silicone PSA composition
from example 1F. The silicone PSA tablet tested for pH effect
contained 20 weight percent of silicone PSA BIO PSA 7-4202 and 80
weight percent of acetaminophen.
[0048] The conditions for the dissolution study in this example is
similar to that explained in Example III, except one study was
performed using dissolution medium of simulated gastric fluid at
about pH 1.2. The rate of acetaminophen release from 20 weight
percent silicone PSA tablet in either about pH 1.2 or about pH 6.8
dissolution medium was evaluated and compared. The result shown in
Table 4 indicates that the release rate of acetaminophen from
silicone PSA tablet does not change due to the dissolution medium
pH.
Example V
Release of Acetaminophen from Silicone PSA Tablets Compressed Using
Different Compression force
[0049] The effect of compression force on the release rate of
acetaminophen from silicone PSA tablets obtained was evaluated
using dissolution medium pH simulated intestinal fluid at about pH
6.8. The compression force used for making silicone PSA tablet is
shown in Table 5 along with the corresponding release rate of
acetaminophen from the silicone PSA tablets. The silicone PSA
tablet tested for pH effect contained 20 weight percent of silicone
PSA BIO PSA 7-4202 and 80 weight percent of acetaminophen.
TABLE-US-00001 Example VA VB VC Polymer Silicone Silicone Silicone
% w/w polymer 20 20 20 % w/w APAP 80 80 80 Compression force (kN)
3.5 6.1 8.7 Silicone here is Bio-PSA 7-4202 amine compatible
adhesive resin from Dow Corning
[0050] The conditions for the dissolution study in this example is
similar to that explained in Example III. The rate of acetaminophen
release from 20 weight percent silicone PSA tablet compressed at
three different compression force was evaluated in about pH 6.8
dissolution medium and compared. The results are shown in Table 5.
The results indicate that the compression force does not affect the
release rate of acetaminophen from silicone PSA tablets.
Example VI
Release of Acetaminophen from Silicone PSA Tablets in Bio Relevant
Dissolution Medium
[0051] The effect of dissolution medium composition on drug release
from silicone PSA tablet was determined using silicone PSA
composition from example 1F. The silicone PSA tablet tested for pH
effect contained 20 weight percent of silicone PSA BIO PSA 7-4202
and 80 weight percent of acetaminophen compressed using 6.1 kN
compression force.
[0052] The conditions for the dissolution study in this example is
similar to that explained in Example III, except the composition of
the dissolution medium. Bio relevant dissolution medium are
commonly used to evaluate the effect of presence of bile salts on
drug release. Fed and fasted state bio relevant dissolution medium
are especially relevant for studying the inertness of controlled
release polymer. The rate of acetaminophen release from 20 weight
percent silicone PSA tablet in either 10% ethanol solution, fed or
fasted state bio relevant dissolution medium was evaluated and
compared. The results are shown in Table 6. The results indicate
that the release rate of acetaminophen from silicone PSA tablet
does not significantly change due to the dissolution medium
composition.
Example VII
Release of Acetaminophen and Tramadol Hydrochloride from Silicone
PSA Tablets
[0053] The effect of addition of another drug in the solid tablet
matrix may be evaluated by changing the composition of the silicone
PSA tablet. The compositions in Example VII are shown in table
below. Tramadol hydrochloride was added using the procedure as
described in example III. The release rate of acetaminophen and
tramadol hydrochloride was evaluated in this example in simulated
intestinal dissolution medium at about pH 6.8. The dissolution
testing conditions are similar to that described in Example III.
The silicone PSA tablet tested contained 20 weight percent of
silicone PSA BIO PSA 7-4202, about 8.7 weight percent tramadol
hydrochloride and about 71.7 weight percent of acetaminophen
compressed using 6.1 kN compression force. The results are shown in
Table 7 below. The concentration of tramadol hydrochloride and
acetaminophen from the dissolution samples were determined using a
HPLC method. A C18 HPLC column was used to quantitate both drugs in
the dissolution samples at 270 nm, using about 40 volume percent
acetonitrile in 60 volume percent of 0.05% w/v trifluoroacetic acid
aqueous mobile phase. The result for release rate for tramadol
hydrochloride and acetaminophen indicates that silicone PSA is able
to sustain release rate of two drugs when mixed in same tablet.
Also, the release rate of both drugs tramadol hydrochloride and
acetaminophen remain unchanged from the silicone PSA tablet
described in this invention. This shows an improvement in oral
matrix, where the release rate of a drug is unchanged on addition
of another drug by changing the composition of the tablet. The
improvement in this said invention will allow those skilled in the
art to decrease in time to optimize the formulation and decreases
the variable involved in controlling drug release rate.
Example VIII
Release of Acetaminophen from Silicone PSA Tablets Containing
Surfactants
[0054] Silicone PSA tablet compositions according to the present
invention are shown below in the amounts of components in weight
percent. The compositions are made using procedure described in
Example VIII. The tablets were prepared using the process described
in Example III.
TABLE-US-00002 Components VIIIA VIIIB VIIIC VIIID Silicone PSA 10
10 10 10 Acetaminophen 80 80 80 80 Capmul 50 10 -- -- -- Tefose1500
-- 10 -- -- Brij98 -- -- 10 -- Myrj53' -- -- -- 10 Silicone here is
Bio-PSA 7-4202 amine compatible PSA resin from Dow Corning
Capmul 50 here is glyceryl monoleate obtained from Abitec
Corporation Tefose1500 here is PEG stearate from Gattefosse Brij 98
here is Polyoxyethylene (20) Oleyl Ether from Sigma Aldrich Myrj53
here is Polyethylene 50 stearate from Croda
[0055] Release of acetaminophen from silicone tablets described in
VIIIA-D is shown below in Table 8. The procedure for determining
acetaminophen drug release rate from these tablets was described in
Example III. Addition of surfactants in silicone matrix changes the
release rate of acetaminophen in comparison to the silicone tablet
without surfactant being present in the composition. The
surfactants shown herein are examples. Change in release rate may
be possible with other excipients, which act as surface active
agents. Addition of surfactants to silicone PSA matrix changes the
release rate depending on the type of surfactant used.
Example IX
Release of Acetaminophen from Silicone PSA Tablets Containing
Excipients
[0056] Silicone PSA tablet compositions according to the present
invention are shown below in the amounts of components in weight
percent. The compositions are made using procedure described in
Example IX A-D. The tablets were prepared using the process
described in Example III.
TABLE-US-00003 Components IXA IXB IXC IXD IXD Silicone PSA 20 20 20
10 10 Acetaminophen 80 60 60 90 80 Mannitol -- 20 20 -- -- PVP K90
-- -- 20 -- -- Tris -- -- -- -- 10 Silicone here is Bio-PSA 7-4202
amine compatible adhesive resin from Dow Corning
[0057] Release of acetaminophen from silicone tablets described in
1.times.A-D is shown in Table 9. Addition of excipients in the
silicone matrix does not change the release rate of acetaminophen
in comparison to the silicone tablet without excipients being
present. The excipients shown herein are examples. Commonly known
excipients to those in the art may also be substituted in the
silicone matrix to obtain sustained release tablet containing
medicament.
Example X
Effect of Mechanical Stress on Release from Silicone Tablet
[0058] The effect of mechanical agitation on drug release from
silicone PSA tablet was determined using silicone PSA composition
from example 1F. The silicone PSA tablets tested for pH effect
contained about 20 weight percent of silicone PSA and about 80
weight percent of acetaminophen compressed using 6.1 kN compression
force. The results were compared to tablets prepared using 20
weight percent ethyl cellulose and 80 weight percent acetaminophen.
Three different silicone PSAs with varying resin/polydimethyl
siloxane ratio were prepared using procedure described in example
III and compared. The three different silicone PSAs BioPSA 7-4102,
7-4202 and 7-4302 vary in their extent of adhesion to a
substrate.
[0059] The conditions for the dissolution study in this example is
similar to that explained in Example III for (-) without mechanical
agitation. Effect of mechanical agitation of performed using
procedure described by Garbacz and Weitschies. Program 3 of the
novel stress test apparatus was used to evaluate the effect of
mechanical stress on drug release. Pressure waves and 100 rpm
rotation were used to induce stress on tablets at predetermined
time points and drug release determined. The results for
acetaminophen drug release using USP apparatus 1 (-) and in stress
test apparatus (+) is shown in Table 10. The results indicate that
silicone PSA tablets do not show effect of mechanical stress on
drug release. In comparison, ethyl cellulose tablets show burst
release when subjected to mechanical stress in comparison to
tablets without being subjected to mechanical stress. This effect
of preventing burst release on application of mechanical stress is
an improvement from current literature. Silicone adhesive matrix
tablets are shown to provide robust mechanism of controlling drug
release.
Example XI
Release of Verapamil Hydrochloride from Silicone PSA Tablets
[0060] The effect of dissolution medium pH on drug release from
silicone PSA tablet containing weakly basic drug verapamil
hydrochloride was determined using USP apparatus 1 dissolution
apparatus at about pH 1.2 and about pH 6.8. Verapamil hydrochloride
was present in 80 weight percent and silicone PSA was present in 20
weight percent. Tablets were prepared using procedure described in
example III. The silicone PSA tablet tested for pH effect contained
20 weight percent of silicone PSA BIO PSA 7-4202 and 80 weight
percent of verapamil hydrochloride. The effect of dissolution
medium pH on drug release from ethyl cellulose tablet was tested
for comparison.
[0061] The conditions for the dissolution study in this example is
similar to that explained in Example III, except one study was
performed using dissolution medium of simulated gastric fluid at
about pH 1.2 and one in simulated intestinal fluid about pH 6.8.
The rate of verapamil hydrochloride release from 20 weight percent
silicone PSA or ethyl cellulose tablets in either about pH 1.2 or
about pH 6.8 dissolution medium was evaluated and compared. The
results are shown in Table 11. The results indicate that the
release of verapamil hydrochloride from silicone PSA tablets is not
affected by the change in the dissolution medium pH. In comparison,
glassy rigid polymer tablet prepared using ethyl cellulose shows
that verapamil hydrochloride release is dependent on the pH of the
dissolution medium.
Example XII
Release of Different Medicaments from Silicone PSA Tablets
[0062] Silicone PSA tablet compositions according to the present
invention are shown below in the amounts of components in weight
percent. The compositions are made using procedure described in
Example XII.
TABLE-US-00004 Components XIIA XIIB XIIC XIID Silicone PSA 20 20 20
20 Diclofenac sodium 80 -- -- -- Sodium salicylate -- 80 -- -- BSA
-- -- 80 -- Tramadol HCl -- -- -- 80 Silicone here is Bio-PSA
7-4202 amine compatible adhesive resin from Dow Corning
[0063] Release of various drugs from silicone tablets described in
XIIA-D are shown below in Table 12. It is possible to prepare
tablets containing medicaments with different physicochemical
properties using silicone PSA. Sustained release of various
medicaments is shown from results obtained in Table 12 below. The
dissolution study was described in detail in example III.
Example XIII
Release of Verapamil Hydrochloride from Acrylate Pressure Sensitive
PSA Tablets
[0064] Tablet compositions according to the example XIII are shown
in tablet below. The procedure used to prepare this composition is
described in detail in Example III. The tablets were 500 mg total
weight and similar dimensions as described in example III. The
effect of dissolution medium pH on drug release from acrylate PSA
tablet containing weakly basic drug verapamil hydrochloride was
determined using USP apparatus 1 dissolution apparatus at about pH
1.2 and about pH 6.8. Verapamil hydrochloride was present in 80
weight percent and acrylate PSA was present in 20 weight percent.
Tablets were prepared using procedure described in example III. The
acrylate PSA tablet was tested for pH effect. The acrylate tablet
composition was about 20 weight percent of DURO_TAK 87-202A
acrylate PSA and about 80 weight percent of verapamil
hydrochloride.
[0065] The conditions for the dissolution study in this example is
similar to that explained in Example III, except one study was
performed using dissolution medium of simulated gastric fluid at
about pH 1.2 and one in simulated intestinal fluid about pH 6.8.
The rate of verapamil hydrochloride release from 20 weight percent
acrylate PSA in either about pH 1.2 or about pH 6.8 dissolution
medium was evaluated and compared. The results are shown in Table
13. The results indicate that the release of verapamil
hydrochloride from acrylate PSA tablets is not affected by the
change in the dissolution medium pH. In comparison, glassy rigid
polymer tablet prepared using ethyl cellulose shows that verapamil
hydrochloride release is dependent on the pH of the dissolution
medium.
TABLE-US-00005 Components XIII Acrylate PSA 20 Verapamil
hydrochloride 80 Acrylate PSA here is acrylate polymer DURO_TAK
87-202A obtained from Henkel corporation
Example XIV
Release of Dilcofenac Sodium from Silicone Tablet Containing
PEG3400
[0066] In this example, diclofenac sodium tablets were prepared
using procedure described in Example III. Effect of addition of
solubilizing agent polyethylene glycol on diclofenac sodium drug
release from silicone PSA may be evaluated. The effect of addition
of calcium phosphate, dibasic on diclofenac sodium was also
evaluated. The compositions of silicone PSA tablets are shown in
table below.
[0067] The conditions for the dissolution study in this example is
similar to that explained in Example III, in simulated intestinal
fluid about pH 6.8. The rate of diclofenac sodium release from 20
weight percent silicone PSA containing different excipients was
evaluated and compared. The results are shown in Table 14. The
results indicate that the release of diclofenac sodium is increased
by the addition of excipients such as mannitol, calcium phosphate
or polyethylene glycol.
TABLE-US-00006 Components XIVA XIVB XIVC XIVD Silicone PSA 20 20 20
20 Diclofenac sodium 80 40 40 40 Mannitol 0 40 -- -- Calcium
phosphate, dibasic -- -- 40 -- PEG 8000 -- -- -- 40 Silicone here
is Bio-PSA 7-4202 amine compatible adhesive resin from Dow
Corning
Example XV
Release of Dexamethasone from Silicone Tablet and Addition of
Cyclodextrin Such as 2-Hydropropyl Cyclodextrin
[0068] In this example, dexamethasone tablets were prepared using
procedure described in Example III. Effect of addition of
solubilizing agent hydroxypropyl-beta-cyclodextrin on dexamethasone
drug release from silicone PSA may be evaluated. The effect of
addition of surfactant on dexamethasone was also evaluated. The
compositions of silicone PSA tablets are shown in table below.
[0069] The conditions for the dissolution study in this example is
similar to that explained in Example III, in simulated intestinal
fluid about pH 6.8. The rate of dexamethasone release from 20
weight percent silicone PSA containing different excipients was
evaluated and compared. The results are shown in Table 15. The
results indicate that the release of dexamethasone can be increased
by addition of excipients such as 2-hydroxypropyl-beta-cyclodextrin
or surfactant such as Brij98.
TABLE-US-00007 Components XVA XVB XVC Silicone PSA 10 10 10
Dexamethasone 1.2 1.2 1.2 Mannitol 88.8 78.8 78.8 Hydroxypropyl
beta-cyclodextrin -- 10 -- Brij 98 -- -- 10 Silicone here is
Bio-PSA 7-4202 amine compatible adhesive resin from Dow Corning
[0070] While various embodiments of the present invention have been
described above, it should be understood that they have been
presented by ay of example, and not limitation. It will be apparent
to persons skilled in the relevant art(s) that various changes in
form and detail can be made therein without departing from the
scope(s) of the present invention. This, embodiments of this
present invention should not be limited by any of the above
described exemplary embodiments, but should be defined only in
accordance with the following claims and their equivalents.
TABLE-US-00008 TABLE 1 APAP Polymer Example Polymer (% w/w) (% w/w)
1A Silicone 99 1 1B Silicone 97.5 2.5 1C Silicone 95 5 1D Silicone
90 10 1E Silicone 85 15 1F Silicone 80 20
TABLE-US-00009 TABLE 2 Example 1A 1B 1C 1D 1E 1F 2 Polymer Silicone
Silicone Silicone Silicone Silicone Silicone EC % w/w 1 2.5 5 10 15
20 20 polymer % w/w 99 97.5 95 90 85 80 80 APAP Tensile 0.020 0.025
0.042 0.080 0.106 0.511 -- strength % 66.1 33.9 0.2 0.0 0.0 0.0 4.8
Fria- bility Contact 88.2 90.2 96.8 89.5 90.1 89.1 44.1 angle (Deg)
Silicone here is Bio-PSA 7-4202 amine compatible adhesive resin
from Dow Corning EC here is Ethyl cellulose, 48% ethoxy content
from International Specialty Polymers Inc
TABLE-US-00010 TABLE 3 Silicone adhesive Example (w/w) 0.5 h 1 h 2
h 4 h 8 h 12 h 24 h 1A 1 32.1 58.9 92.0 98.9 99.2 99.3 101.5 1B 2.5
22.3 32.6 54.6 86.5 97.3 100.0 100.1 1C 5 31.9 31.9 46.9 66.4 93.7
99.1 102.6 1D 10 18.0 29.9 43.8 59.1 82.7 93.9 100.7 1E 15 17.3
27.1 37.8 50.3 66.9 79.0 106.1 1F 20 11.8 17.8 24.1 36.0 50.7 63.7
82.2 Silicone here is Bio-PSA 7-4202 amine compatible adhesive
resin from Dow Corning
TABLE-US-00011 TABLE 4 0 h 0.5 h 1 h 2 h 4 h 8 h 12 h 24 h pH 1.2
0.0 13.1 20.3 28.2 39.5 52.0 60.0 74.0 pH 6.8 0.0 11.8 17.8 24.1
36.0 50.7 63.7 82.2
TABLE-US-00012 TABLE 5 Exam- ple Force 0 h 0.5 h 1 h 2 h 4 h 8 h 12
h 24 h VA 3.5 kN 0.0 12.9 18.9 27.4 38.9 56.1 68.9 93.6 VB 6.1 kN
0.0 15.3 21.1 30.0 41.2 57.2 70.7 97.3 VC 8.7 kN 0.0 11.8 17.8 24.1
36.0 50.7 63.7 82.2
TABLE-US-00013 TABLE 6 0 h 0.5 h 1 h 2 h 4 h 8 h 12 h 24 h 10%
Ethanol 0.0 15.5 24.8 30.0 48.4 77.9 88.4 89.2 FesSIF 0.0 17.4 25.3
38.5 53.6 72.7 82.0 104.8 FasSIF 0.0 15.8 23.3 43.0 52.5 69.9 77.7
103.4
TABLE-US-00014 TABLE 7 0 h 0.5 h 1 h 2 h 4 h 8 h 12 h 24 h Tramadol
HCl 0.0 15.8 23.2 32.1 43.4 56.8 68.3 89.4 APAP 0.0 13.5 22.6 31.9
44.8 61.1 74.3 86.0
TABLE-US-00015 TABLE 8 Example 0 h 0.5 h 1 h 2 h 4 h 6 h 8 h 10 h
12 h 24 h 8A 0.0 15.2 23.3 36.6 54.9 66.9 74.2 80.6 85.4 102.9 8B
0.0 8.3 11.2 15.3 20.4 24.6 27.6 30.2 32.3 43.3 8C 0.0 25.4 38.2
58.2 84.7 96.2 98.4 99.1 99.4 102.2 8D 0.0 18.9 27.2 39.0 56.0 66.8
75.6 82.6 90.4 100.6
TABLE-US-00016 TABLE 9 Example 0 h 0.5 h 1 h 2 h 4 h 6 h 8 h 10 h
12 h 24 h IXA 0.0 11.8 17.8 24.1 36.0 -- 50.7 -- 63.7 82.2 IXB 0.0
12.2 18.1 25.8 36.8 -- 50.7 -- 60.8 84.7 IXC 0.0 14.2 16.3 20.6
29.0 43.6 56.9 83.3 -- -- IXD 0.0 18.0 29.9 43.8 59.1 73.1 82.7
93.9 100.7 -- IXE 0.0 18.3 28.8 41.9 58.9 69.9 81.3 92.3 101.7
--
TABLE-US-00017 TABLE 10 Mechanical Polymer stress 0 h 1 h 2 h 4 h 8
h 12 h EC - 0 56.2 79.3 120.1 174.4 242.5 EC + 0.0 32.5 69.5 223.1
405.5 412.4 PSA 7-4102 - 0.0 78.4 98.2 187.5 240.5 244.3 PSA 7-4102
+ 0.0 27.1 80.5 131.1 204.2 254.5 PSA 7-4202 - 0.0 82.1 128.3 175.1
230.4 302.4 PSA 7-4102 + 0.0 58.1 85.1 126.0 187.7 -- PSA 7-4302 -
0.0 83.4 113.0 171.6 277.4 301.2 PSA 7-4302 + 0.0 33.1 56.3 85.9
139.8 167.4 PSA 7-4102 here is Bio-PSA 7-4102 amine compatible
adhesive resin from Dow Corning PSA 7-4202 is Bio-PSA 7-4202 amine
compatible adhesive resin from Dow Corning PSA 7-4302 here is
Bio-PSA 7-4302 amine compatible adhesive resin from Dow Corning EC
here is Ethyl cellulose, 48% ethoxy content from International
Specialty Polymers Inc
TABLE-US-00018 TABLE 11 Disso- Poly- lution mer medium % Polymer pH
w/w 0 h 0.5 h 1 h 2 h 4 h 8 h 12 h EC 1.2 20 0.0 25.7 37.1 49.6
70.7 93.4 107.6 EC 6.8 20 0.0 16.5 29.6 34.1 50.2 65.0 79.7
Silicone 1.2 20 0.0 29.7 31.7 48.9 69.0 93.6 103.8 Silicone 6.8 20
0.0 26.8 33.3 45.8 67.5 90.2 98.0
TABLE-US-00019 TABLE 12 Example 0 h 0.5 h 1 h 2 h 4 h 8 h 12 h 24 h
XIIA 0.0 5.7 6.5 8.3 11.3 17.0 23.5 30.4 XIIB 0.0 32.6 47.7 71.7
78.5 81.2 80.3 79.6 XIIC 0.0 28.9 48.1 65.6 71.7 73.7 74.0 76.7
XIID 0.0 55.4 71.5 99.2 105.8 105.3 106.1 --
TABLE-US-00020 TABLE 13 0 h 0.5 h 1 h 2 h 4 h 8 h 12 h pH 1.2 0.0
16.2 23.0 38.3 69.7 81.0 84.9 pH 6.8 0.0 16.7 27.7 53.6 73.6 75.2
76.6
TABLE-US-00021 TABLE 14 0 h 0.25 h 0.5 h 0.75 h 1 h 1.5 h 2 h 3 h 4
h 6 h 8 h 12 h 24 h XIVA 0.0 6.7 5.9 6.7 10.4 8.4 9.3 10.4 12.6
14.4 17.3 22.6 31.0 XIVB 0.0 7.9 10.0 12.5 14.9 18.1 21.4 25.7 30.1
36.0 41.2 48.1 60.1 XIVC 0.0 1.8 3.4 4.5 5.3 7.2 8.9 11.5 14.4 18.1
21.9 29.2 42.4 XIVD 0.0 11.3 15.9 18.9 20.8 23.4 28.0 36.4 44.9
54.3 59.6 68.4 77.4
TABLE-US-00022 TABLE 15 Example 0 h 0.5 h 1 h 2 h 4 h 8 h 12 h 24 h
XVA 0.0 23.6 37.6 44.0 44.3 45.7 45.6 51.1 XVB 0.0 6.5 12.4 14.1
19.8 23.3 30.0 32.3 XVC 0.0 32.6 45.6 62.7 69.8 79.4 81.0 90.8
* * * * *